Retroviruses are a class of viruses having a single-stranded RNA genome that reproduce in a host organism by generating a DNA copy of its genome by action of a virally coded RNA-directed DNA polymerase, reverse transcriptase. Reverse transcriptase can construct double-stranded DNA molecules from the single stranded RNA of the viral genome. The most notorious retrovirus is the human immunodeficiency virus (HIV), which is responsible for the generally fatal disease, acquired immune deficiency syndrome (AIDS). Although the disease itself has been studied greatly, it has been treated only with limited success.
A number of nucleosides have been utilized in the treatment of HIV infections. 3′-azido-3′-deoxythymidine (AZT) is a prime example, although its ability to completely reverse the progress of the disease remains unconfirmed. A number of 2′,3′-dideoxynucleoside analogs have also been reported to exhibit activity against HIV, including 3′-deoxy-2′,3′-didehydrothymidine (d4T), the carbocyclic analog of 2′,3′-dideoxy-2′,3′-didehydroguanosine (Carbovir), 2′,3′-dideoxycytidine (ddC), 3′-azido-2′,3′-dideoxyguanosine (AZG), 2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxy-2′,3′-didehydrocytidine (d4C), 3′-fluoro-2′,3′-dideoxyadenosine, 3′-fluoro-3′-deoxythymidine and 3′-azido-2′,3′-dideoxyuridine. Some of these analogs, including ddC, are presently used as anti-HIV agents. Among the dideoxynucleosides, ddC has been shown to be a potent inhibitor of HIV.
Although research has concentrated on developing an effective treatment for AIDS and certain potent anti-HIV nucleoside analogs have been synthesized and characterized, an ideal drug has not been found. The major limitation in providing an optimized drug for treatment against retroviral infections, including HIV, remains the inability to provide the necessary anti-viral activity while maintaining minimal toxicity to the host cell (mammalian DNA).
The viral replication process is believed to be an important event in the progress of AIDS. It is also believed that the enzyme reverse transcriptase plays an essential role in the replication and life cycle of HIV, and consequently, in furthering the progress of the disease. The development of potential drugs for AIDS have therefore attempted to target this enzyme, especially because of it is absent in the uninfected host cell.
Anti-retroviral nucleoside derivative compounds such as azidothymidine (AZT), dideoxyinosine (ddI) and dideoxycytidine (ddC) function by inhibiting the activity of HIV reverse transcriptase. The mode of action for such compounds primarily requires their conversion to the corresponding 5′-triphosphates, thereby enabling them to function as substrates for reverse transcriptase. Upon incorporation of such chain terminating nucleoside triphosphates, DNA synthesis of the HIV cDNA genome is terminated, thus inhibiting replication by the virus. A common problem with chain terminating nucleosides is that they exhibit significant toxicity toward non-infected healthy cells. This is presumably due to the fact that they also function as chain terminators for human DNA polymerases and therefore, interfere with normal DNA replication. The introduction of an azido functionality at the C3′-position of the furanosyl ring in AZT provides some discrimination, such that it is not accepted as well by human DNA polymerases. Nevertheless, AZT is one of the most effective anti-HIV compounds presently in clinical use.